Neutrophils Resist Ferroptosis and Promote Breast Cancer Metastasis through Aconitate Decarboxylase 1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA893601 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22024860_1.fastq.gz | Fastqsanger.gz | |||
| SRR22024860_2.fastq.gz | Fastqsanger.gz | |||
| SRR22024861_1.fastq.gz | Fastqsanger.gz | |||
| SRR22024861_2.fastq.gz | Fastqsanger.gz | |||
| SRR22024862_1.fastq.gz | Fastqsanger.gz |
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Project description:Lung metastasis is the principal cause of breast cancer-related mortality. Neutrophils have emerged as an important component of the tumor microenvironment (TME), supporting tumor proliferation and mediating immunosuppression. Here, we show that aconitate decarboxylase 1 (Acod1) is highly expressed in tumor-infiltrating neutrophils and promotes breast cancer lung metastasis by supporting neutrophil survival in the TME. Acod1 expression is regulated by tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) through the JAK/STAT signaling pathway and CCAAT/enhancer-binding protein beta (C/EBPβ) transcription factor activity. Acod1 loss in tumor-infiltrating neutrophils leads to ferroptosis-like cell death, resulting in decreased frequency of neutrophils in the TME. Mechanistically, itaconate, the product of Acod1, activates nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in upregulated antioxidant responses and decreased lipid-reactive oxygen species. Genetical deletion of Acod1 in neutrophils suppresses lung metastasis of breast cancer in mouse models by decreasing neutrophil-lymphocyte ratio and elevating cytotoxic T cell response. Importantly, genetic targeting of Acod1 enhances the anti-tumor efficacy of immune checkpoint blockade. Overall, our findings reveal a mechanism of how immunosuppressive neutrophils survive in the harsh TME and support Acod1-targeting approaches for cancer treatment.
2023-09-13 | GSE216425 | GEO
Project description:The Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Here, we explore the role of endogenous ACOD1-itaconate pathway in the activation of BMDM after imiquimod treatment.
2024-04-17 | GSE250384 | GEO
Project description:Aconitate decarboxylase 1 mediates acute airway inflammatory response to environmental exposures
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Project description:Brucellosis is one of the most widespread bacterial zoonoses worldwide. Here, our aim was to identify the effector mechanisms controlling the early stages of intranasal infection with Brucella in C57BL/6 mice. During the first 48 hours of infection, alveolar macrophages (AMs) are the main cells infected in the lungs. Using RNA sequencing, we identified the aconitate decarboxylase 1 gene (Acod1; also known as Immune responsive gene 1), as one of the genes most upregulated in murine AMs in response to B. melitensis infection at 24 hours post-infection. Upregulation of Acod1 was confirmed by RT-qPCR in lungs infected with B. melitensis and B. abortus. We observed that Acod1-/- C57BL/6 mice display a higher bacterial load in their lungs than wild-type (wt) mice following B. melitensis or B. abortus infection, demonstrating that Acod1 participates in the control of pulmonary Brucella infection. The ACOD1 enzyme is mostly produced in mitochondria of macrophages, and converts cis-aconitate, a metabolite in the Krebs cycle, into itaconate. Dimethyl itaconate (DMI), a chemically-modified membrane permeable form of itaconate, has a dose-dependent inhibitory effect on Brucella growth in vitro. Interestingly, modelling studies suggest the binding of itaconate into the binding site of isocitrate lyase. DMI does not inhibit multiplication of the isocitrate lyase deletion mutant ∆aceA B. abortus in vitro. Finally, we observed that, unlike the wt strain, the ∆aceA B. abortus strain multiplies similarly in wt and Acod1-/- C57BL/6 mice. These data suggest that bacterial isocitrate lyase might be a target of itaconate in AMs.
2021-09-21 | GSE180699 | GEO
Project description:Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice
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Project description:Background: Environmental lipopolysaccharide (LPS) and microbial component-enriched organic dusts cause significant lung diseases. These environmental exposures induce the recruitment and activation of distinct lung monocyte/macrophage subpopulations involved in disease pathogenesis. Given monocyte/macrophage activation is tightly linked to metabolism, the objective of these studies was to determine the role of the immunometabolic regulator, aconitate decarboxylase 1 (ACOD1), in environmental exposure-induced lung inflammation. Methods: Wild-type (WT) mice were intratracheally instilled (I.T.) with 10 ug LPS or saline. Whole lungs were profiled using bulk RNA sequencing or sorted to isolate monocyte/macrophage subpopulations. Sorted subpopulations were then characterized transcriptomically using a NanoString innate immunity multiplex array 48 hours post-exposure. Next, WT and Acod1-/- mice were instilled with LPS, 25% organic dust extract (ODE), or saline with serum, bronchoalveolar lavage fluid (BALF), and lung tissues collected. BALF metabolites of the tricarboxylic acid (TCA) cycle were quantified by mass-spectrometry. Cytokines/chemokines and tissue remodeling mediators were quantitated by ELISA. Lung immune cells were characterized by flow cytometry. Whole body plethysmography was performed 3 hours post-LPS with WT and Acod1-/- mice. Results: By bulk sequencing, Acod1 was one of the most significantly upregulated genes following LPS (vs. saline) exposure of murine whole lungs. Transcriptomic profiling of sorted lung monocyte/macrophage subpopulations corroborated Acod1 significance. Acod1-/- mice treated with LPS (vs. WT) demonstrated decreased BALF levels of itaconate, TCA cycle reprogramming, decreased BALF neutrophils, increased lung CD4+ T cells, decreased BALF and lung levels of TNF-a, and decreased BALF CXCL1. In comparison, Acod1-/- mice treated with ODE (vs. WT) demonstrated decreased serum pentraxin-2, BALF levels of itaconate, lung total cell, neutrophil, monocyte, and B cell infiltrates with decreased BALF levels of TNF-a, IL-6, and decreased lung CXCL1. Mediators of tissue remodeling (TIMP1, MMP8, MMP9) were also decreased in the LPS-exposed Acod1-/- mice, with MMP-9 also decreased in the ODE-exposed Acod1-/- mice. Lung function assessments demonstrated a blunted response to LPS-induced airway hyper-responsiveness in Acod1-/- mice. Conclusion: Acod1 is robustly upregulated in the lungs following LPS-exposure and encodes a key immunometabolic regulator. ACOD1 mediates the pro-inflammatory response to acute inhaled, environmental LPS and organic dust exposure-induced lung inflammation.
2024-10-15 | GSE267022 | GEO
Project description:Wild type (WT) and Aconitate decarboxylase 1 knockout (Acod1-/-) BMDM treated with Imiquimod for 12h
| PRJNA1053787 | ENA
Project description:Sleepiness is commonly associated with neuroinflammation; however, the underlying neuroregulatory mechanisms remain unclear. Previous research suggests that the paraventricular thalamus (PVT) plays a crucial role in regulating sleep‐wake dynamics; thus, neurological abnormalities in the PVT may contribute to neuroinflammation-induced sleepiness. To test this hypothesis, we performed electroencephalography recordings in mice treated with lipopolysaccharide (LPS) and found that the mice exhibited temporary sleepiness lasting for 7 days. Using the Fos-TRAP method, fiber photometry recordings, and immunofluorescence staining, we detected temporary PVT neuron hypoactivation and microglia activation from day 1 to day 7 post-LPS treatment. Combining the results of bulk and single-cell RNA sequencing, we found upregulation of aconitate decarboxylase 1 (Acod1) in PVT microglia post-LPS treatment. To investigate the role of Acod1, we manipulated Acod1 gene expression in PVT microglia via stereotactic injection of short hairpin RNA adenovirus. Knockdown of Acod1 exacerbated inflammation, neuronal hypoactivation, and sleepiness. Itaconate is a metabolite synthesized by the enzyme encoded by Acod1. Finally, we confirmed that exogenous administration of an itaconate derivative, 4-octyl itaconate, could inhibit microglia activation, alleviate neuronal dysfunction, and relieve sleepiness. In summary, our findings highlight PVT’s role in inflammation-induced sleepiness and suggest Acod1 as a potential therapeutic target for neuroinflammation.
2024-10-23 | GSE280081 | GEO
Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.
2022-09-24 | GSE213861 | GEO
Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.
2022-09-19 | GSE205371 | GEO